Wildlife reservoirs of various strains of rabies virus continue to expand with the major threat of humans contracting fatal rabies in North America being due to unrecognized exposure to a variant associated with species of bats that range throughout the continent. The emergence of the first cases of cryptic rabies over the past decade, most often caused by infection with silver-haired bat associated rabies viruses (SHBRV), serves notice that critical events in rabies pathogenesis, that are important therapeutic intervention, remain poorly understood. These are the focus of the current proposal and include: 1. the unknown mechanism of invasion of SHBRV from peripheral sites to the CNS; 2. the contribution of selected factors expressed by host cells to virus replication and spread in the CNS; 3. the processes whereby only certain neutralizing antibodies gain access to infected CNS tissue and are protective. The proposed studies are based on observations, relevant to these events, recently made in our laboratories: 1. rabies viruses associated with the cryptic form of the disease may infect dendritic cells; 2. host genes encoding the neurotrophic growth factors neuroleukin (NLK) and fibroblast growth factor homologous factors (FHF)-4 are active in the rabies virus-infected brain whereas the majority of host genes are downregulated; 3. monoclonal antibodies differ in their protective capacity and access across the blood-brain barrier (BBB) can be provided by cellular immune mechanisms. In the three specific aims we propose to: 1. determine whether the apparent infection of dendritic cells by SHBRV is productive and may carry virus into contact with the nervous system, using in vitro dendritic cell culture and in vivo models; 2. assess the contribution of NLK and FHF-4 1a and lb to the replication and spread of rabies virus in the CNS, by molecular and immunohistochemical analysis of infected brain tissue and factor addition to primary neuron cultures infected with rabies virus; and 3. elucidate the contributions of antibody specificity and structure and known mechanisms of BBB permeability enhancement to immune protection, using molecular engineering of rabies virus-specific antibodies, assays of BBB function, and assessment of antibody entry into CNS tissues. The goal of these studies is to provide a comprehensive understanding of the course of rabies from infection to death, and, ultimately, improved modalities for treatment of rabies infection and neurotrophic virus infection in general.